Medical Care |

Medical Care

##SEVER##

/i/ijepp.in1.html

Les antibiotiques sont produits sous des formes pharmaceutiques telles que des pilules acheter du amoxil.

elles permettent d'injecter la quantité de préparation strictement nécessaire.

Ijepp.in


IJEPP 2015, 1 (1), 29-36
Moumita et al
Review Article
A Brief Review on ProproteinConvertaseSubtilisin/Kexin Type 9
Moumita Ghosh Laskar 1, 2* and Amit Laskar 1, 2
1Metabolism Unit, Department of Endocrinology, Metabolism and Diabetes and 2Molecular Nutrition Unit, Department of Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, C2-94 S-141 86 Stockholm, Sweden Abstract
Proproteinconvertasesubtilisin/ kexin type 9 (PCSK9) is a newly identified secreted protein which plays a vital role in cholesterol homeostasis. PCSK9 increases low-density lipoprotein cholesterol (LDL-C) in plasma by inhibiting its clearance via inducing degradation of low-density lipoprotein receptor (LDLR). In humans, PCSK9 level is modulated by factors such as age, gender, gene mutations, hormones, diet, plant products, fasting and diurnal rhythm. Recent research has proposed inhibition of PCSK9 as a beneficial therapeutic approach to control dyslipidemia, importantly in hypercholesterolemia patients. Thus inhibition of PCSK9 appears to be a considerable promising approach to minimize cardiovascular risk these days. In this review, we acknowledge the recent development in the field of PCSK9. We also highlight the reason behind its choice as a novel therapeutic target to combat LDL-C related imbalances in cardiovascular diseases; an area of focus, increasingly explored by researchers in collaboration with pharmaceutical companies. Key words: Proproteinconvertasesubtilisin/ kexin type 9 (PCSK9), Low density lipoprotein
(LDL), hormones, diet and PCSK9 inhibitor.
*Corresponding author:
Moumita Ghosh Laskar
Metabolism Unit, Department of Endocrinology, Metabolism and Diabetes, Department of Medicine,
Karoli nskaInstitutet at Karolinska University Hospital Huddinge, C2-94.
S-141 86 Stockholm, Sweden
E-mail:
oumita.ghosh@ki.se Quick Response Code:
IJEPP 2015, 1 (1), 29-36
Moumita et al
Since then, it has been now well evidenced that PCSK9 plays a vital role in cholesterol metabolism In humans, an increased risk for development of by regulating hepatic LDLR. Though it abundantly atherosclerosis and cardiovascular events is expresses in liver, but it is also present to a lesser extent in the small intestine, kidney, and central cholesterol metabolismCholesterol is a molecule nervous system. In human, PCSK9 gene is present of fundamental importance for normal cell on chromosome 1p32.3. PCSK9 strongly correlates function, and serves as a precursor for steroid hormones and bile acids. The liver has a crucial dyslipidemia and atherosclerosis. Structurally, role in cholesterol homeostasis. In the liver, alone with a 30 amino acid signal sequence, cholesterol is converted to bile acids that are PCSK9 contains a prodomain (amino acid 31-152), secreted into bile together with free cholestero a catalytic domain (amino acids 153-425) and a cysteine histidine rich C-terminal domain (amino cholesterol. Cells also acquire cholesterol by de acids 426-692)Over expression or gain of novo synthesis. In blood, plasma cholesterol is function (GOF) mutation of PCSK9 gene leads to transported within lipoproteins such as high-density hypercholesterolemia whereas, loss of function (LOF) mutations of PCSK9 gene lead to lipoproteins (LDL), very low-density lipoproteins hypocholesterolemia and reduced cardiac risk. (VLDL) and chylomicrons. Various surface receptors such as low-density lipoprotein receptor PCSK9 and its role on LDLR
(LDLR), scavenger receptor class B type1 (SRB-1) and very-low-density (VLDLR) are involved in the cellular uptake of proproteinconvertase family, is a secreted protein which presumably is secreted from the liver. Within hepatic cells, PCSK9 is synthesized as a precursor (72 Kda) which undergoes autocatalytic especially LDL-cholesterol (LDL-C) are linked to cleavage and produces 2 products, the prosegment cardiovascular diseIn human blood, 70% of and the mature PCSK9 (63 KDa). This the cholesterol is within LDL particlesMost autocatalytic cleavage is required for maturation of plasma LDL is taken up by liver while the rest is PCSK9 and also for its trafficking from ER to distributed to peripheral tissues and to the adrenals and gonadsModulation of hepatic LDL circulationBefore secretion, mature PCSK9 receptors (LDLRs) plays a vital role for LDL-C post-translational level in plasma by influencing the clearance of modifications such as N-glycosylation, sulphation LDL-C from circulation. LDLR numbers are and phosphorylation. On the cellular membrane, the catalytic domain of circulating PCSK9 binds to transcriptional (via the sterol regulatory element- the epidermal growth factor precursor homology binding protein (SREBP) -2 pathway) and b) domain-A (EGF-A) of the LDLR in a calcium- post-transcriptional dependent manner.Then the complex of LDLR/PCSK9 is internalized within the cell via (PCSK9) mechanismsThe very important clathrin-mediated endocytosis thus entering the role of post-transcriptional regulation by PCSK9 endosomal pathwayThe bonding affinity of was established during last decade. PCSK9 induces LDLR/PCSK9 complex is increased in the low pH the degradation of hepatic LDLR, thereby elevating of endosomAs a result of changes in the cholesterol levels in plasma. Higher PCSK9 levels conformation of LDLR its recycle back to cell correlate with cardiovascular complications and thus, inhibiting PCSK9 could be beneficial for LDLR/PCSK9 is then directed to the lysosome and minimizing cardiovascular risks in human. destined for lysosomal degradation. Plasma levels of PCSK9 generally correlate positively with the plasma LDL-C. PCSK9 induces lysosomal LDLR degradation after binding to the LDLR Previously known as neural apoptosis-regulated (Figure 1). As a result, it down-regulates cellular convertase 1, PCSK9 was discovered in 2003.
LDLR numbers thereby diminishing the cellular IJEPP 2015, 1 (1), 29-36
Moumita et al
uptake of LDL particles and increasing plasma regulated during menstruation cycle depending on the estrogen levels in fertile femHowever, a intracellular PCSK9 could also lead the lysosomal study in Chinese population suggests otherwise, degradation of LDLR. Within the hepatocyte, where no such correlation was found before LDLR transport toward to the cellular membrane, the prosegment PCSK9 binds to LDLR Testosterone, a male sex hormone reduces hepatic and forms the prosegment PCSK9 /LDLR complex PCSK9 mRNA and protein and also circulating which is then directed from Golgi to the lysosome PCSK9 in pig whereas a study in human has for degradation However, the underlying shown that circulating PCSK9 is not related to testosterone in males. degradation of LDLR is not fully understood. Thyroid hormones such as tri-iodo-thyronine (T3) PCSK9 relation to age, gender and other
and thyroxine (T4) are synthesized in the thyroid metabolic factors
gland. These hormones are proven to be the major regulators It is known that plasma cholesterol, especially the Hypothyroidism is strongly associated with levels of LDL-C increases in human with age. In enhanced levels of plasma total and LDL females, this increase of LDL-C is much prominent cholesterol whereas in hyperthyroidism, it is vice after menopause. Studies have shown that PCSK9 versa. Results indicate that PCSK9 level is lower in levels also increase with age in a healthy patients with hyperthyroidism. Treatment with population, and it is higher in females then in eprotirome, a thyroid hormone supplement reduces males.It is also proposed that PCSK9 is one of the reasons for age-related induction of LDL-C at least in females. In addition, PCSK9 has Glucagon and Insulin, two important hormones been shown to be positively correlated with LDL- involved in carbohydrate homeostasis, have also C, total-C, triglyceride, insulin, body mass index shown to be correlated with PCSK9.Glucagon (BMI), and glucose and with cholesterol synthesis is a peptide hormone produce from alpha cells of the pancreas, increases concentration of glucose in blood whereas insulin, another peptide hormone Hormonal effects on PCSK9
produced from beta cells of the pancreas regulates carbohydrate metabolism and enhances glucose Studies have shown that LDL-C metabolism is absorption from blood to musStudies have modulated by hormones such as estrogen (E2), shown that these two hormones may influence Testosterone (T), adrenocorticotropic hormone PCSK9 in human.
(ACTH), thyroid hormone (TH), Growth hormone (GH) and glucagon in human and in animals.
Dietary effects on PCSK9
Studies have also shown that hormones such as estrogen, testosterone, thyroid hormone and Dietary nutrition has also shown to regulate PCSK9 in animals and humans. Several studies have found transcriptionally post-transcriptionally the sterols influences PCSK9 mRNA expressions animals, as well as in human. via SREBP2 pathway. Mediterranean diet and diet containing vegetable polyunsaturated fatty Estrogen, a female sex hormone has shown to acids (PUFAs) reduce circulating PCSK9 in reduce hepatic PCSK9 mRNA and protein levels in human. In humans, it has been also described animFurthermore, in humans, supra- that high fructose containing diet induces an physiological levels of estrogen (prior to in vitro increase in plasma PCSK9 concentration.
fertilization) reduce plasma PCSK9 and LDL PCSK9 is also affected by fasting and follows a cholesterol levelsHowever, from post-hoc diurnal rhythm.Additionally, Berberine, an analysis of postmenopausal females, taking isoquinoline plant alkaloid, found in plants such as estrogen supplement indicates that exogenous Berberis vulgaris, Coptis chinensis, Berberis estrogen therapy has failed to reduce circulating aristata inhibit hepatic and circulating PCSK9 PCSK9 in postmenopausal womenIt has been thereby reducing cardiovascular risk. reported that PCSK9 and LDL-C may also be PCSK9 as a therapeutic target


IJEPP 2015, 1 (1), 29-36
Moumita et al
Figure 1: A) Degradation of LDLR and involvement of PCSK9; B) LDL-C clearance and recycling of
Proproteinconvertasesubtilisin/kexin type 9- (PCSK9). Table 1: Pharmaceutical advancement in development of PCSK9 inhibitors
Treatment approaches to
Pharmaceutical companies
Present status and
inhibit PCSK9
development
Monoclonal antibodies
Sanofi/Regeneron FDA approved, July 2015 FDA approved, August 2015 Phase III ongoing Phase II completed Phase I completed Alnylam Pharmaceuticals Phase I completed Phase I recruiting Mimetic peptides
Adnectin
Phase I completed Small molecules
Shifa Biomedical Corp Preclinical completed Abbreviations: Proproteinconvertasesubtilisin/kexin type 9- (PCSK9); Food and drug administration (FDA).
IJEPP 2015, 1 (1), 29-36
Moumita et al
Inhibition of circulating and intercellular PCSK9 is Zannis VI, Chroni A, Krieger M. Role of a novel therapeutic approach for the treatment of apoA-I, ABCA1, LCAT, and SR-BI in the dyslipidemAs discussed earlier, loss of biogenesis of HDL. J. Mol. Med. 2006, function (LOF) mutations of PCSK9 gene reduces the cardiac risk by decreasing cholesterol levels Wood D, De Backer G, Faergeman O, Moreover, most commonly used lipid lowering Graham I, Mancia G, Pyorala K. drugs such as statins, the inhibitor of cholesterol Prevention of coronary heart disease in biosynthesis via SREBP2 pathway, and Ezetimibe, clinical practice: recommendations of the the only cholesterol absorption inhibitor, reported Second Joint Task Force of European and to induce PCSK9 in human, motivated the need for other Societies on Coronary Prevention. Atherosclerosis. 1998, 140:199-270. pharmaceutical market. Interestingly, the approach Goldstein JL, Brown MS. Atherosclerosis: of PCSK9 inhibition either by monoclonal antibody or via some other approach such as mimetic hypothesis. Metabolism. 1977, 26:1257- peptides, adnectin, siRNA and small molecules turns out to be a promising treatment for Williams KJ, Tabas I. The response-to- cardiovascular disease. These molecules are retention hypothesis of atherogenesis undergoing clinical trials in different phases (Table reinforced. Curr. Opin. Lipidol. 1998, Smith JR, Osborne TF, Goldstein JL, Brown MS. Identification of nucleotides responsible for enhancer activity of sterol Results and progress of different clinical trials, as mentions in table 1, indicate that PCSK9 inhibitors lipoprotein receptor gene. The Journal of alone or combination with other lipid lowering biological chemistry. 1990, 265:2306-10. drugs could be a successful treatment for Maxwell KN, Breslow JL. Adenoviral- hypercholesterolemia in near future. mediated expression of Pcsk9 in mice results in a low-density lipoprotein DISCLOSURES
receptor knockout phenotype. Proc. Natl. There is no conflict to disclose. Acad. Sci. U. S. A. 2004, 101:7100-5. Park SW, Moon YA, Horton JD. Post- REFERENCES
transcriptional regulation of low density Blackett PR, Sanghera DK. Genetic lipoprotein receptor protein by proprotein determinants of cardiometabolic risk: a convertase subtilisin/kexin type 9a in proposed model for phenotype association mouse liver. The Journal of biological and interaction. J Clin Lipidol. 2013, 7:65- chemistry. 2004, 279:50630-8. Abifadel M, Varret M, Rabes JP, Allard Dietschy JM, Turley SD, Spady DK. Role D, Ouguerram K, Devillers M, Cruaud C, of liver in the maintenance of cholesterol Benjannet S, Wickham L, Erlich D, Derre and low density lipoprotein homeostasis in A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf humans. J. Lipid Res. 1993, 34:1637-59. JM, Luc G, Moulin P, Weissenbach J, Prat Gibbons GF, Wiggins D, Brown AM, A, Krempf M, Junien C, Seidah NG, Hebbachi AM. Synthesis and function of Boileau C. Mutations in PCSK9 cause very-low-density Biochem. Soc. Trans. 2004, 32:59-64. hypercholesterolemia. Nat. Genet. 2003, Twisk J, Gillian-Daniel DL, Tebon A, Wang L, Barrett PH, Attie AD. The role of Seidah NG, Benjannet S, Wickham L, the LDL receptor in apolipoprotein B Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M. The investigation. 2000, 105:521-32. secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC- IJEPP 2015, 1 (1), 29-36
Moumita et al
1): liver regeneration and neuronal Farnier M. PCSK9 inhibitors. Curr. Opin. differentiation. Proc. Natl. Acad. Sci. U. Lipidol. 2013, 24:251-8. S. A. 2003, 100:928-33. Maxwell KN, Fisher EA, Breslow JL. Cohen J, Pertsemlidis A, Kotowski IK, Overexpression of PCSK9 accelerates the Graham R, Garcia CK, Hobbs HH. Low degradation of the LDLR in a post- LDL cholesterol in individuals of African descent resulting from frequent nonsense Proc. Natl. Acad. Sci. U. S. A. 2005, mutations in PCSK9. Nat. Genet. 2005, Cui Q, Ju X, Yang T, Zhang M, Tang W, Duff CJ, Hooper NM. PCSK9: an Chen Q, Hu Y, Haas JV, Troutt JS, Pickard RT, Darling R, Konrad RJ, Zhou hypercholesterolemia. Expert Opin Ther H, Cao G. Serum PCSK9 is associated Targets. 2011, 15:157-68. with multiple metabolic factors in a large Bergeron N, Phan BA, Ding Y, Fong A, Han Chinese population. Atherosclerosis. 2010, 213:632-6. Subtilisin/Kexin Type 9 Inhibition: A Ghosh M, Galman C, Rudling M, Angelin B. Influence of physiological changes in Reducing Cardiovascular Disease Risk. Circulation. 2015, 132:1648-66. PCSK9 and LDL cholesterol. J. Lipid Res. Seidah NG. PCSK9 as a therapeutic target of dyslipidemia. Expert Opin Ther Lakoski SG, Lagace TA, Cohen JC, Targets. 2009, 13:19-28. Horton JD, Hobbs HH. Genetic and Zhang DW, Lagace TA, Garuti R, Zhao Z, metabolic determinants of plasma PCSK9 McDonald M, Horton JD, Cohen JC, endocrinology and metabolism. 2009, convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of Persson L, Henriksson P, Westerlund E, low density lipoprotein receptor decreases Hovatta O, Angelin B, Rudling M. Endogenous estrogens lower plasma degradation. The Journal of biological PCSK9 and LDL cholesterol but not Lp(a) chemistry. 2007, 282:18602-12. or bile acid synthesis in women. Kwon HJ, Lagace TA, McNutt MC, Arterioscler. Thromb. Vac. Biol. 2012, Horton JD, Deisenhofer J. Molecular basis for LDL receptor recognition by PCSK9. Bonde Y, Breuer O, Lutjohann D, Sjoberg Proc. Natl. Acad. Sci. U. S. A. 2008, S, Angelin B, Rudling M. Thyroid hormone reduces PCSK9 and stimulates Fisher TS, Lo Surdo P, Pandit S, Mattu M, bile acid synthesis in humans. J. Lipid Santoro JC, Wisniewski D, Cummings Res. 2014, 55:2408-15. RT, Calzetta A, Cubbon RM, Fischer PA, Galman C, Angelin B, Rudling M. Tarachandani A, De Francesco R, Wright Prolonged stimulation of the adrenals by SD, Sparrow CP, Carfi A, Sitlani A. corticotropin suppresses hepatic low- Effects of pH and low density lipoprotein lipoprotein receptors and increases plasma receptor regulation. The Journal of biological chemistry. 2007, 282:20502-12. Nassoury N, Blasiole DA, Tebon Oler A, Ooi TC, Raymond A, Cousins M, Favreau Benjannet S, Hamelin J, Poupon V, C, Taljaard M, Gavin C, Jolly EE, Malone McPherson PS, Attie AD, Prat A, Seidah S, Eapen L, Chretien M, Mbikay M, NG. The cellular trafficking of the secretory proprotein convertase PCSK9 testosterone, estradiol and circulating and its dependence on the LDLR. Traffic. interventional studies in humans. Clinica IJEPP 2015, 1 (1), 29-36
Moumita et al
chimica acta; international journal of postmenopausal women: A randomised clinical chemistry. 2015, 446:97-104. study. Vascul Pharmacol. 2015 Persson L, Galman C, Angelin B, Rudling Richard C, Couture P, Desroches S, M. Importance of proprotein convertase Benjannet S, Seidah NG, Lichtenstein AH, subtilisin/kexin type 9 in the hormonal and Lamarche B. Effect of the Mediterranean dietary regulation of rat liver low-density diet with and without weight loss on 2009, 150:1140-6. homeostasis in men with the metabolic Guo W, Fu J, Chen X, Gao B, Fu Z, Fan syndrome. The British journal of nutrition. H, Cui Q, Zhu X, Zhao Y, Yang T, Fan D, 2012, 107:705-11. Zhou H. The effects of estrogen on serum Cariou B, Langhi C, Le Bras M, Bortolotti level and hepatocyte expression of M, Le KA, Theytaz F, Le May C, PCSK9. Metabolism. 2015, 64:554-60. Guyomarc'h-Delasalle B, Zair Y, Kreis R, Cai Z, Xi H, Pan Y, Jiang X, Chen L, Cai Boesch C, Krempf M, Tappy L, Costet P. Y, Zhu K, Chen C, Xu X, Chen M. Effect Plasma PCSK9 concentrations during an of testosterone deficiency on cholesterol oral fat load and after short term high-fat, metabolism in pigs fed a high-fat and high-fat high-protein and high-fructose high-cholesterol diet. Lipids Health Dis. diets. Nutr. Metab. 2013, 10:4. Browning JD, Horton JD. Fasting reduces Ferner H. [The insular alpha and beta cells as the source of the antagonistic principles subtilisin/kexin type 9 and cholesterol glucagon and insulin]. Mikroskopie. 1951, biosynthesis in humans. J. Lipid Res. 2010, 51:3359-63. Calandra S, Tarugi P, Speedy HE, Dean Persson L, Cao G, Stahle L, Sjoberg BG, Troutt JS, Konrad RJ, Galman C, Wallen Mechanisms and genetic determinants H, Eriksson M, Hafstrom I, Lind S, Dahlin regulating sterol absorption, circulating M, Amark P, Angelin B, Rudling M. LDL levels, and sterol elimination: implications for classification and disease subtilisin kexin type 9 has a diurnal risk. J. Lipid Res. 2011, 52:1885-926. rhythm synchronous with cholesterol Costet P, Cariou B, Lambert G, Lalanne F, synthesis and is reduced by fasting in Lardeux B, Jarnoux AL, Grefhorst A, humans. Arterioscler. Thromb. Vac. Biol. Staels B, Krempf M. Hepatic PCSK9 2010, 30:2666-72. expression is regulated by nutritional Cameron J, Ranheim T, Kulseth MA, status via insulin and sterol regulatory Leren TP, Berge KE. Berberine decreases element-binding protein 1c. The Journal of PCSK9 expression in HepG2 cells. biological chemistry. 2006, 281:6211-8. Atherosclerosis. 2008, 201:266-73. Bjermo H, Iggman D, Kullberg J, Pirillo A, Catapano AL. Berberine, a plant Dahlman I, Johansson L, Persson L, alkaloid with lipid- and glucose-lowering Berglund J, Pulkki K, Basu S, Uusitupa properties: From in vitro evidence to M, Rudling M, Arner P, Cederholm T, clinical studies. Atherosclerosis. 2015, Ahlstrom H, Riserus U. Effects of n-6 PUFAs compared with SFAs on liver fat, Benjannet S, Hamelin J, Chretien M, Seidah NG. Loss- and gain-of-function PCSK9 variants: cleavage specificity, controlled trial. The American journal of dominant negative effects, and low density clinical nutrition. 2012, 95:1003-12. lipoprotein receptor (LDLR) degradation. Graversen CB, Lundbye-Christensen S, The Journal of biological chemistry. 2012, Thomsen B, Christensen JH, Schmidt EB. Marine n-3 polyunsaturated fatty acids Cui CJ, Li S, Li JJ. PCSK9 and its subtilisin kexin type 9 levels in pre- and IJEPP 2015, 1 (1), 29-36
Moumita et al
international journal of clinical chemistry. 2015, 440:79-86.

Source: http://www.ijepp.in/journal/G_20_I.pdf

Untitled

Die Zeitung der KleintierKlinik Hannover Parvovirose – immer auch wenn die Welt heut- noch eine aktuelle zutage eine digitale ist und wir mit Nachrichten so-zusagen im Sekundentakt Erkrankung überfl utet werden, halten wir an unserer tie-risch gut! in Zeitungsform fest. Somit freuen wir uns, Sie wieder mit wichtigen Informationen zu Tieren und aus

Petroleum csg

Health, Safety, Environment and Community Petroleum Management System Heat Stress Management PETROLEUM CSG HSEC MANAGEMENT SYSTEM PROCEDURE HEAT STRESS MANAGEMENT Petroleum HSEC Procedure No: PHSE-13-P10 Date: May 9, 2012 Revision: 0.1 Owner: Kim Phillips, Occupational Health and Hygiene Manager